The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms. XRCC1 has no known enzymatic activity, but depends on protein to protein interactions to carry out its functional role in DNA repair. Therefore, use of a biological system such as the mouse to help define function related to expression of an observable tumor phenotype when challenged with a carcinogen is a major means of investigating XRCC1 function. Azoxymethane (AOM) is an alkylating agent and a well-established carcinogen in mice with a spectrum of pre-tumor, pre-malignant, and malignant lesions in the colon and to a lesser extent the liver. It also serves as a prototype for alkylating agents present in the environment that present potentially significant exposure risks. Our hypothesis is that cancer susceptibility to AOM can be influenced by XRCC1 haploinsufficiency and single nucleotide polymorphisms R194W and R280H. Information generated from our proposed studies could be used to help design clinically relevant studies to identify individuals or groups that may be at increased cancer risk for specific environmental conditions. PUBLIC HEALTH RELEVANCE: The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms.